Patients with primary brain cancers and brain metastases from other cancers are difficult to treat, as most systemically administered therapeutic agents do not reach intracranial disease. The blood-brain barrier (BBB) limits many small molecule drugs and essentially all macromolecular therapeutic agents (peptides, proteins, nucleic acids) from reaching the brain. While some intracranial tumors can eventually breach the BBB, this project focuses on reaching disease that is accessible via an intact BBB. We propose to create a targeted nanoparticle (NP) that crosses an intact BBB to deliver therapeutic agents to intracranial tumors in mouse models of the human disease. Here, we will initiate our investigations using mouse models of glioblastoma (GBM). The Davis group has translated two different NPs into clinical studies for a variety of cancers (CRLX101[1] ? contains a small molecule drug, and CALAA-01 [2,3]- contains siRNA). The NP CALAA-01 utilizes transferrin for surface receptor targeting agent and siRNA as the therapeutic entity. Recently, Davis? group showed how transferrin-containing NPs can cross an intact BBB in mice if the NP properties are properly designed [4]. Here, we will exploit those findings to create targeted NPs that can transport single or multiple therapeutic agents (the central NSBCC theme) across the BBB and into GBM tumors from systemic administrations in mice. Successful completion of this project will provide therapeutic modalities to address intracranial disease. Because sub-100 nm NPs will be the delivery vehicles, inclusion of multiple therapeutic entities (informed via the results that emerge from Project 4) within the NPs will allow combination strategies to be employed. Although work will begin with delivery of a single small molecule drug, success will enable combinations of multiple small molecule drugs, and extensions to individual and combinations of macromolecular therapeutic agents.